WO2003/066635 describes a number of diazabicycle derivatives having NK1 antagonist activity, including the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (otherwise known as orvepitant).
Orvepitant, otherwise known as 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide has the following chemical structure (I).

Hereinafter any reference to orvepitant refers to the compound (I).
Orvepitant may also be known as:
CAS Index name 1-Piperidinecarboxamide, N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-4-[(8aS)-hexahydro-6-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl]-N-methyl-, (2R,4S)
and
IUPAC name:
(2R,4S)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-piperidinecarboxamide.
A preferred salt of the compound(I) is its hydrochloride salt which is otherwise known as orvepitant hydrochloride.
A further preferred salt of the compound(I) is its maleate salt which is otherwise known as orvepitant maleate.
WO02009/124996 describes a new crystalline form of orvepitant maleate namely anhydrous crystalline form (Form1).
The compound (I), pharmaceutically acceptable salts thereof are described in the aforementioned specifications as antagonists of tachykinin receptors, including substance P (SP) and other neurokinin receptors, both in vitro and in vivo and are thus of use in the treatment of conditions mediated by tachykinins, including SP and other neurokinins.
Particularly, the compound (I), and pharmaceutically acceptable salts or solvates thereof are described as useful in the treatment of central nervous system (CNS) disorders.
We have now surprisingly found that the compound (I) or pharmaceutically acceptable salts thereof are also useful in the treatment of pruritus.
Particularly, we have found that the compound (I) or pharmaceutically acceptable salts thereof are useful in the treatment of chronic pruritus.
Pruritus can be defined as an unpleasant sensation that evokes the desire to scratch.
Thus according to International Classification of Diseases (ICD-10-CM) pruritus is defined as intense itching sensation that produces the urge to rub or scratch the skin to obtain relief.
Pruritus is a physiological perception within the sensory neuronal network in the skin which, along with pain and physical or mechanical stimuli, serves as a warning system against potential bodily threats and it is an integral part of patient's symptoms in numerous dermatological and systemic diseases. Pruritus can have a dramatic impact on quality of life and can worsen the general condition and capacity of the patient considerably.
Only in the past decade has pruritus received attention in scientific research and despite the significant advancements made in understanding this condition, there are still many underlying mechanisms in its pathophysiology that remain unknown (Ständer S et al. Journal of the Germany Society of Dermatology (2011), 9:456-463).
In recent years, pruritus has been defined as an autonomous, pain-independent sensation, and itch-specific neurons, mediators, spinal neurons, and cortical areas have been identified.
Pruritus is mediated by free nerve endings of non-myelinated nerve fibres that are located at the dermoepidermal junction and within the epidermis. For a number of diseases that involve itching, such as atopic dermatitis, prurigo nodularis, and allergic contact dermatitis, it has been suggested that the increased production and release of “nerve growth factor” (NGF) from resident skin cells such as keratinocytes or mast cells leads to an increase in intraepidermal “itch fibres” in the skin possibly leading to the exacerbation of pruritus (Ikoma A et al. Nat Rev Neuroscience (2006), 7(7): 535-547).
Along with the nerve fibres, mast cells in the skin also play a central role in mediating pruritus. Mast cells can release numerous biologically active mediators as a result of specific (receptor-mediated) or non-specific (e.g., via mechanical or chemical) stimuli (Metz and Maurer. Trends Immunol (2007), 28(5):234-241). Some of these mast cell products are characterized by their potent itch-inducing effect. Examples of mast cells products include histamine, protease, lipid mediators such as Leukotriene B4 and prostaglandins.
There are also a few substances that either cause pruritus without directly affecting nerve fibres or that mediate pruritus indirectly through activation of skin mast cells. Although these are broadly referred to as histamine liberators, the activation of mast cells as described above can also lead to the release of other pruritus-inducing substances. Among the most relevant mast cell activators in pruritic diseases are neuropeptides such as vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and SP.
Particularly, SP is hypothesised to induce itch, following its release from sensory nerves, by activation of dermal mast cells and other cell types (including cells of the immune system) resulting in the liberation of histamine (mast cells) and other pro-inflammatory mediators (Divito S J et al. Immunol Res (2011), 50(2-3):195-201). Mast cells have been shown to accumulate in the lesional skin of cancer patients treated with the epidermal growth factor receptor inhibitor erlotinib and it has been proposed that the activation of these mast cells by SP accounts for the pruritus experienced by subjects administered such epidermal growth factor receptor inhibitors (Gerber P A et al. J Am Acad Dermatol (2010), 63(1):163-5; N Engl J Med (2011), 364(5):486-7). In mice there is some evidence that SP driven pruritus also involves a non-histamine/non-mast cell dependent mechanism since SP induced scratching is neither inhibited by anti-histamines nor in mast cell deficient animals. Skin-scratching is a commonly seen behaviour in patients with pruritus which often exacerbates original lesions. In a mouse model, after skin-scratching stimulation, mast cells significantly de-granulated within several minutes with SP-immunoreactive nerve fibres disappearing immediately from sensory nerve fibres, indicating the quick secretion and depletion of SP; blockade by a NK-1 antagonist suppressed these scratching-induced decreases in SP-immunoreactive nerve fibres (Yamaoka et al. J Dermatol Sci (2007), 48(2):123-132).
It has been also demonstrated that intradermal injection of SP into skin of both animals (Andoh T et al. The Journal of Pharmacology and Experimental Therapeutics (1998), 286(3):1140-1145) and humans (Thomsen J S et al. British J Dermatology (2002), 146(5):792-800) induces itching and scratching. Despite SP being an important neuropeptide mediating pruritus, the clinical efficacy of NK-1 antagonists for the treatment of pruritus has yet to be fully evaluated and elucidated (Tey H L & Yosipovitch G. British Journal Pharmacology (2011), 165:5-17). The symptom of chronic itch represents a worldwide burden in the community as well as in specific populations (Weisshaar E & Dalgard F. Acta Derm. Venereol (2009), 89:339-350). It is desirable to translate these recent improvements in the understanding of the pathophysiology of pruritus into new therapeutics.
Therapeutic options for pruritus are limited and treatment is sub-optimal, there is a requirement for new and effective anti-pruritic drugs to meet the significant unmet need.
Classification of Pruritus
Because pruritus occurs in many diseases of different etiologies, various classification systems for pruritus exist. Pruritus has been recently reclassified by the International Forum for the Study of Itch (IFSI) in 2007 (Ständer S et al. Acta Derm Venereol (2007), 87:291-294).
According to this classification system, pruritus can be distinguished as acute and chronic, with the latter defined as pruritus lasting 6 or more weeks and it has been classified into the following groups.
Group I. The first group is named pruritus on primary diseased, inflamed skin.
Many skin diseases are accompanied by itch. They comprise inflammatory, infectious, or autoimmune cutaneous diseases, genodermatoses, drug reactions, dermatoses of pregnancy and skin lymphomas, all of which lead to specific skin changes described elsewhere.
The underlying diseases according to Group I include Category I.
Category I Pruritus associated with or due to a dermatological disorder, disease or condition such as:
Inflammatory dermatoses including atopic dermatitis/eczema, psoriasis, irritant/contact dermatitis, irritant/contact eczema, urticaria, dry skin, adverse drug reactions, scars, pruritus ani, pruritus scroti, pruritus vulvae and ‘invisible dermatoses’;
Infectious dermatoses including mycotic, bacterial and viral infections and folliculitis, scabies, pediculosis, arthropod reactions and insect bites;
Autoimmune dermatoses including bullous dermatoses, especially dermatitis herpetiformis Duhring, bullous pemphigoid and dermatomyositis;
Genodermatoses including Darier's disease, Hailey-Hailey disease, ichthyoses, Sjögren-Larsson syndrome and epidermolysis bullosa pruriginosa;
Dermatoses of pregnancy including polymorphic eruption of pregnancy, pemphigoid gestationis and prurigo gestationis;
Neoplasms including cutaneous T-cell-lymphoma (especially erythrodermic variants and Sézary syndrome and mycosis fungoides), cutaneous B-cell lymphoma and leukaemic infiltrates of the skin.
Group II. Pruritus on primary non-diseased, non-inflamed skin.
Patients with pruritic diseases of systemic, neurological or psychosomatic/psychiatric origin experience pruritus without any skin lesions except for possible secondary scratch lesions. Systemic diseases leading to itch include endocrine and metabolic disorders, infections, haematological and lymphoproliferative diseases, solid neoplasms and drug-induced pruritus.
The underlying diseases according to Group II include Category II-IV.
Category II. Pruritus associated with or due to a systemic disorder, disease or condition such as:
Endocrine and metabolic diseases including chronic renal failure, liver diseases with or without cholestasis, hyperthyroidism, malabsorption, perimenopausal pruritus and diabetes mellitus;
Infectious diseases including HIV-infection, HCV infection, chicken-pox, helminthosis and parasitosis;
Haematological and lymphoproliferative diseases including iron deficiency, polycythaemia vera, Hodgkin's disease, Non-Hodgkin's lymphoma and plasmocytoma;
Visceral neoplasms including solid tumours of the cervix, prostate, or colon and carcinoid syndrome;
Pregnancy including pruritus gravidarum with and without cholestasis;
Drug-induced pruritus such as opioids, ACE-inhibitors, amiodarone, hydrochlorothiazid, estrogens, simvastatin, hydroxyethyl starch, allopurinol; section also includes chemotherapy-induced pruritus as a result of treatment with agents such as kinase inhibitors (for example epidermal growth factor receptor inhibitors like erlotinib and cetuximab).
Category III. Pruritus associated with or due to a neurogenic disorder, disease or condition such as:
Neurogenic origin (without neuronal damage) including hepatic itch with increased endogenous μ-opioids (dis-inhibition of itch);
Neuropathic diseases (neuronal damage causes itch) including multiple sclerosis, neoplasms, abscesses, cerebral or spinal infarcts, brachioradial pruritus, nostalgia paresthetica, post-herpetic neuralgia, vulvodynia and small fibre neuropathy.
Category IV. Pruritus associated with or due to a somatoform disorder, disease or condition such as psychiatric/psychosomatic diseases including depression, anxiety disorders, obsessive-compulsive disorders, schizophrenia, tactile hallucinosis and fatigue.
Group III. Pruritus presenting with severe chronic secondary scratch lesions.
Chronic pruritus frequently leads to mechanical reactions, such as scratching, rubbing or pinching. Scratching may induce variable damage of the skin, presenting as excoriations, crusts, lichenification, papules and nodules. These lesions may resolve leaving hyper- or hypo-pigmentation and atrophic scars of the skin. Several lesions in different stages and sizes may co-exist in patients with chronic pruritus. Some of these clinical manifestations are summarized using terms such as lichen simplex chronicus, lichen Vidal, lichen amyloidosus, macular amyloidosus, and prurigo nodularis. All of these represent secondary acquired lesions induced by chronic scratching.
The underlying origin may be either a skin or systematic diseases in Category I to IV.
The following categories have been also identified:
Category V. Pruritus associated with overlapping of disorders, diseases or conditions described in Categories I to IV.
Category VI. Pruritus associated with or due to an unknown disorder, disease or condition.